Nucleophile

In chemistry, a nucleophile (literally nucleus lover as in nucleus and phile) is a reagent that forms a chemical bond to its reaction partner (the electrophile) by donating both bonding electrons. ¹ Because nucleophiles donate electrons, they are by definition Lewis bases (see acid-base reaction theories). All molecules or ions with a free pair of electrons can act as nucleophiles, although negative ions (anions) are more potent than neutral reagents. Neutral nucleophilic reactions with solvents such as alcohols and water are named solvolysis.

Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge on an element and displaces the group it is bonded to.

Nucleophilic is an adjective that describes the affinity of a nucleophile to the nuclei, while nucleophilicity or nucleophile strength refers to the nucleophilic character. Nucleophilicity is often used to compare an atom's relative affinity to another's.

In general, in a row across the periodic table, the more basic the ion (the higher the pK_a of the conjugate acid), the more reactive it is as a nucleophile. In a given group, polarizability is more important in the determination of the nucleophilicity: the easier it is to distort the electron cloud around an atom or molecule, the more readily it will react. e.g., the iodide ion (I⁻) is more nucleophilic than the fluoride ion (F⁻).

An ambident nucleophile is one that can attack from two or more places, resulting in two or more products. For example, the thiocyanate ion (SCN⁻) may attack from either the S or the N. For this reason, the S_N2 reaction of an alkyl halide with SCN⁻ often leads to a mixture of RSCN (an alkyl thiocyanate) and RNCS (an alkyl isothiocyanate). Similar considerations apply in the Kolbe nitrile synthesis.

The terms nucleophile and electrophile were introduced by Christopher Kelk Ingold in 1929,² replacing the terms cationoid and anionoid proposed earlier by A. J. Lapworth in 1925.³

Common examples

In the example below, the oxygen of the hydroxide ion donates an electron to bond with the carbon at the end of the bromopropane molecule. The bond between the carbon and the bromine then undergoes heterolytic fission, with the bromine atom taking the donated electron and becoming the bromide ion (Br⁻): The picture is incorrect, because a Sn2 reaction occurs by backside attack. This means that the hydroxide ion attacks the carbon atom from the other side, exactly opposite the bromine ion. Because of this backside attack, SN2 reactions result in a reversal of the stereochemistry of the electrophile. If the electrophile is chiral, it typically maintains its chirality, though the SN2 product's configuration is flipped as compared to that of the original electrophile.

Carbon nucleophiles

Enols are also carbon nucleophiles. The formation of an enol is catalyzed by acid or base. Enols are ambident nucleophiles, but generally nucleophilic at the alpha carbon atom. Enols are commonly used in condensation reactions, including the Claisen condensation and the aldol condensation reactions.

Oxygen nucleophiles

Sulfur nucleophiles

Sulfur is generally very nucleophilic because of its large size, which makes it easily polarizable, and its lone pairs of electrons (in some cases).

Nitrogen nucleophiles

Nucleophilicity scales

Many schemes have been devised attempting to quantify relative nucleophilic strength. The following empirical data have been obtained by measuring reaction rates for a large number of reactions involving a large number of nucleophiles and electrophiles and linear regression. Nucleophiles displaying the so-called alpha effect are usually omitted in this type of treatment.

Swain-Scott equation

The first such attempt is found in the so-called Swain-Scott equation⁴⁵ derived in 1953:

This free-energy relationship relates the pseudo first order reaction rate constant (in water at 25°C), k, of a reaction, normalized to the reaction rate, k₀, of a standard reaction with water as the nucleophile, to a nucleophilic constant n for a given nucleophile and a substrate constant s that depends on the sensitivity of a substrate to nucleophilic attack (defined as 1 for methyl bromide).

Richie equation

The Richie equation named after its creator and derived in 1972 is another free-energy relationship:⁶⁷⁸

where N⁺ is the nucleophile dependent parameter and k₀ the reaction rate constant for water. In this equation a substrate dependent parameter like s in the Swain-Scott equation is absent. The equation states that two nucleophiles react with the same relative reactivity regardless of the nature of the electrophile which is in violation of the Reactivity–selectivity principle. For this reason this equation is also called the constant selectivity relationship.

In the original publication the data were obtained by reactions of selected nucleophiles with selected electrophilic carbocations such as tropylium cations:

or (not displayed) ions based on Malachite green. Subsequently many other reaction types were described.

Typical Richie N⁺ values (in methanol) are: 0.5 for methanol, 5.9 for the cyanide anion, 7.5 for the methoxide anion , 8.5 for the azide anion and 10.7 for the thiophenol anion. The values for the relative cation reactivities are -0.4 for the malachite green cation, +2.6 for the benzenediazonium cation and +4.5 for the tropylium cation.

Mayr-Patz equation

The second order reaction rate constant k at 20°C for a reaction is related to a nucleophilicity parameter N, an electrophilicity parameter E and a nucleophile-dependent slope parameter s. The constant s is defined as 1 with 2-methyl-1-pentene as the nucleophile.

Many of the constants have been derived from reaction of so-called benzhydrylium ions as the electrophiles:¹⁰

benzhydrylium ions used in the determination of Mayr-Patz equation

and a diverse collection of π-nucleophiles:

Typical N values with s in parenthesis are -4.47 (1.32) for electrophilic aromatic substitution to toluene (1), -1.41 (1.12) for electrophilic addition to 1-phenyl-2-propene (2) and 0.96 (1) for addition to 2-methyl-1-pentene (3), -0.13 (1.21) for reaction with triphenylallylsilane (4), 3.61 (1.11) for reaction with 2-methylfuran (5), +7.48 (0.89) for reaction with isobutenyltributylstannane (6) and +13.36 (0.81) for reaction with the enamine 7.¹¹

With E = -9.15 for the S-methyldibenzothiophenium ion, typical nucleophile values N (s) are 15.63 (0.64) for piperidine, 10.49 (0.68) for methoxide and 5.20 (0.89) for water. In short: nucleophilicities towards sp₂ or sp₃ centers follow the same pattern.

Unified equation

In an effort to unify the above described equations the Mayr equation is rewritten as:¹²

with s_E the electrophile-dependent slope parameter and s_N the nucleophile-dependent slop parameter. This equation can be rewritten in several ways:

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